Search results for: assembly inhibitors

Authors: Vinod Nair, C. Sadasivan

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Beta-lactam antibiotics are the most frequently prescribed medications in modern medicine. The antibiotic resistance by the production of enzyme beta-lactamase is an important mechanism seen in microorganisms. Resistance to beta-lactams mediated by beta-lactamases can be overcome successfully with the use of beta-lactamase inhibitors. New generations of the antibiotics contain mostly synthetic compounds, and many side effects have been reported for them. Combinations of beta-lactam and beta-lactamase inhibitors have become one of the most successful antimicrobial strategies in the current scenario of bacterial infections. Plant-based drugs are very cheap and having lesser adverse effect than synthetic compounds. The synergistic effect of eugenol acetate with beta-lactams restores the activity of beta-lactams, allowing their continued clinical use. It is reported here the enhanced inhibitory effect of phytochemical, eugenol acetate, isolated from the plant Syzygium aromaticum with beta-lactams on beta-lactamase. The compound was found to have synergistic effect with the antibiotic amoxicillin against antibiotic-resistant strain of S.aureus. The enzyme was purified from the organism and incubated with the compound. The assay showed that the compound could inhibit the enzymatic activity of beta-lactamase. Modeling and molecular docking studies indicated that the compound can fit into the active site of beta-lactamase and can mask the important residue for hydrolysis of beta-lactams. The synergistic effects of eugenol acetate with beta-lactam antibiotics may justify, the use of these plant compounds for the preparation of β-lactamase inhibitors against β-lactam resistant S.aureus.

Keywords: betalactamase, eugenol acetate, synergistic effect, molecular modeling

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Authors: Nicky Wilson, Graeme Ralph

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Legacy aerostructure assembly is defined by large components, low build rates, and manual assembly methods. With an increasing demand for commercial aircraft and emerging markets such as the eVTOL (electric vertical take-off and landing) market, current methods of manufacturing are not capable of efficiently hitting these higher-rate demands. This project will look at how legacy manufacturing processes can be rate enabled by taking a holistic view of data usage, focusing on how data can be collected to enable fully integrated digital factories and supply chains. The study will focus on how data is flowed both up and down the supply chain to create a digital thread specific to each part and assembly while enabling machine learning through real-time, closed-loop feedback systems. The study will also develop a bespoke architecture to enable connectivity both within the factory and the wider PLM (product lifecycle management) system, moving away from traditional point-to-point systems used to connect IO devices to a hub and spoke architecture that will exploit report-by-exception principles. This paper outlines the key issues facing legacy aircraft manufacturers, focusing on what future manufacturing will look like from adopting Industry 4 principles. The research also defines the data architecture of a PLM system to enable the transfer and control of a digital thread within the supply chain and proposes a standardised communications protocol to enable a scalable solution to connect IO devices within a production environment. This research comes at a critical time for aerospace manufacturers, who are seeing a shift towards the integration of digital technologies within legacy production environments, while also seeing build rates continue to grow. It is vital that manufacturing processes become more efficient in order to meet these demands while also securing future work for many manufacturers.

Keywords: Industry 4, digital transformation, IoT, PLM, automated assembly, connected factories

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Authors: Peng Hou

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Natural products produced from marine bacteria serve as an immense reservoir for anti-infective drugs and therapeutic agents. Nowadays, heterologous expression of gene clusters of interests has been widely adopted as an effective strategy for natural product discovery. Briefly, the heterologous expression flowchart would be: biosynthetic gene cluster identification, pathway construction and expression, and product detection. However, gene cluster capture using traditional Transformation-associated recombination (TAR) protocol is low-efficient (0.5% positive colony rate). To make things worse, most of these putative new natural products are only predicted by bioinformatics analysis such as antiSMASH, and their corresponding natural products biosynthetic pathways are either not expressed or expressed at very low levels under laboratory conditions. Those setbacks have inspired us to focus on seeking new technologies to efficiently edit and refractor of biosynthetic gene clusters. Recently, two cutting-edge techniques have attracted our attention - the CRISPR-Cas9 and Gibson Assembly. By now, we have tried to pretreat Brevibacillus laterosporus strain genomic DNA with CRISPR-Cas9 nucleases that specifically generated breaks near the gene cluster of interest. This trial resulted in an increase in the efficiency of gene cluster capture (9%). Moreover, using Gibson Assembly by adding/deleting certain operon and tailoring enzymes regardless of end compatibility, the silent construct (~80kb) has been successfully refactored into an active one, yielded a series of analogs expected. With the appearances of the novel molecular tools, we are confident to believe that development of a high throughput mature pipeline for DNA assembly, transformation, product isolation and identification would no longer be a daydream for marine natural product discovery.

Keywords: biosynthesis, CRISPR-Cas9, DNA assembly, refactor, TAR cloning

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Authors: Eman Alzahrani, Hala M. Abo-Dief, Ashraf T. Mohamed

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The present work is aimed at examining carbon steel oil pipelines corrosion using three natural extracts (Eruca Sativa, Rosell and Mango peels) that are used as inhibitors of different concentrations ranging from 0.05-0.1wt. %. Two sulphur compounds are used as corrosion mediums. Weight loss method was used for measuring the corrosion rate of the carbon steel specimens immersed in technical white oil at 100ºC at various time intervals in absence and presence of the two sulphur compounds. The corroded specimens are examined using the chemical wear test, scratch test and hardness test. The scratch test is carried out using scratch loads from 0.5 Kg to 2.0 Kg. The scratch width is obtained at various scratch load and test conditions. The Brinell hardness test is carried out and investigated for both corroded and inhibited specimens. The results showed that three natural extracts can be used as environmentally friendly corrosion inhibitors.

Keywords: inhibition, natural extract, oil pipelines corrosion, sulphur compounds

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Authors: Anthony John Walker, Glen Bright

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The challenge faced by manufactures, when producing custom products, is that each product needs exact components. This can cause work-in-process instability due to component matching constraints imposed on assembly cells. Clearing type flow control policies have been used extensively in mediating server access between multiple arrival processes. Although the stability and performance of clearing policies has been well formulated and studied in the literature, the growth in arrival to departure sequence disorder for each arriving job, across a serving resource, is still an area for further analysis. In this paper, a closed form industrial model has been formulated that characterizes arrival-to-departure sequence disorder through stable manufacturing systems under clearing type flow control policy. Specifically addressed are the effects of sequence disorder imposed on a downstream assembly cell in terms of work-in-process instability induced through component matching constraints. Results from a simulated manufacturing system show that steady state average sequence disorder in parallel upstream processing cells can be balanced in order to decrease downstream assembly system instability. Simulation results also show that the closed form model accurately describes the growth and limiting behavior of average sequence disorder between parts arriving and departing from a manufacturing system flow controlled via clearing policy.

Keywords: assembly system constraint, custom products, discrete sequence disorder, flow control

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Authors: Nigar Kantarci Carsibasi

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Coarse-grained elastic network models, namely Gaussian network model (GNM) and Anisotropic network model (ANM), are utilized in order to investigate the fluctuation dynamics of Murine Double Minute 2 (MDM2), which is the native inhibitor of p53. Conformational dynamics of MDM2 are elucidated in unbound, p53 bound, and non-peptide small molecule inhibitor bound forms. With this, it is aimed to gain insights about the alterations brought to global dynamics of MDM2 by native peptide inhibitor p53, and two small molecule inhibitors (HDM201 and NVP-CGM097) that are undergoing clinical stages in cancer studies. MDM2 undergoes significant conformational changes upon inhibitor binding, carrying pieces of evidence of induced-fit mechanism. Small molecule inhibitors examined in this work exhibit similar fluctuation dynamics and characteristic mode shapes with p53 when complexed with MDM2, which would shed light on the design of novel small molecule inhibitors for cancer therapy. The results showed that residues Phe 19, Trp 23, Leu 26 reside in the minima of slowest modes of p53, pointing to the accepted three-finger binding model. Pro 27 displays the most significant hinge present in p53 and comes out to be another functionally important residue. Three distinct regions are identified in MDM2, for which significant conformational changes are observed upon binding. Regions I (residues 50-77) and III (residues 90-105) correspond to the binding interface of MDM2, including (α2, L2, and α4), which are stabilized during complex formation. Region II (residues 77-90) exhibits a large amplitude motion, being highly flexible, both in the absence and presence of p53 or other inhibitors. MDM2 exhibits a scattered profile in the fastest modes of motion, while binding of p53 and inhibitors puts restraints on MDM2 domains, clearly distinguishing the kinetically hot regions. Mode shape analysis revealed that the α4 domain controls the size of the cleft by keeping the cleft narrow in unbound MDM2; and open in the bound states for proper penetration and binding of p53 and inhibitors, which points to the induced-fit mechanism of p53 binding. P53 interacts with α2 and α4 in a synchronized manner. Collective modes are shifted upon inhibitor binding, i.e., second mode characteristic motion in MDM2-p53 complex is observed in the first mode of apo MDM2; however, apo and bound MDM2 exhibits similar features in the softest modes pointing to pre-existing modes facilitating the ligand binding. Although much higher amplitude motions are attained in the presence of non-peptide small molecule inhibitor molecules as compared to p53, they demonstrate close similarity. Hence, NVP-CGM097 and HDM201 succeed in mimicking the p53 behavior well. Elucidating how drug candidates alter the MDM2 global and conformational dynamics would shed light on the rational design of novel anticancer drugs.

Keywords: cancer, drug design, elastic network model, MDM2

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Authors: A. M. Iordache, S. M. Iordache, V. Barna, M. Elisa, I. C. Vasiliu, C. R. Stefan, I. Chilibon, I. Stamatin, S. Caramizoiu, C. E. A. Grigorescu

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The general objective of the presentation is the development of an e-tongue like sensor based on modified screen printed electrode (SPE) structures with a receptor part made of porphyrins/metalloporphyrins chemically bound to graphene (the sensitive assembly) to act as antennas and “capture” the histamine molecules. Using a single, ultra-sensitive electrochemical sensor, we measured the concentration of histamine, a compound which is strongly connected to the level of freshness in foods (the caution level of histamine is 50 ppm, whereas the maximum accepted levels range from 200 ppm to 500 ppm). Our approach for the chemical immobilization of the porphyrins onto the surface of the graphenes was via substitution reaction: a solution of graphene in SOCl2 was heated to 800C for 6 hours. Upon cooling, the metallo-porphyrins were added and ultrasonicated for 4 hours. The solution was then allowed to cool to room temperature and then centrifuged in order to separate the deposit. The sensitive assembly was drop casted onto the carbon SPE and cyclic voltammetry was performed in the presence of histamine. The reaction is quasi-reversible and the sensor showed an oxidation potential for histamine at 600 mV. The results indicate a linear dependence of concentration of histamine as function of intensity. The results are reproducible; however the chemical stability of the sensitive assembly is low.

Keywords: histamine, cyclic voltammetry, metallo-porphyrin, food freshness

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Authors: Jung-Feng Hsieh, Chu Ze Chen

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Curcumin is the main active compound of turmeric that can inhibit the activities of α-glucosidase and xanthine oxidase (XO). α-Glucosidase and XO inhibitors are widely used to treat patients with diabetes mellitus and gout, respectively; therefore, the objective of this research was to evaluate the inhibitory activities of curcumin and its analogs against α-glucosidase and XO. Our results demonstrated that CM-F had the strongest antioxidant activity with a half-maximal effective concentration (EC50) of 9.39 ± 0.16 μM, which was superior to vitamin E (EC50=17.03 ± 0.09 μM). CM-F also exhibited potent inhibitory activity against XO with an IC50 value of 6.14 ± 0.38 μM and enzyme kinetic results revealed competitive inhibition of XO. We also found that CM-1 and CM-2 inhibited α-glucosidase with IC50 values of 21.06 ± 0.92 μM and 5.95 ± 0.09 μM, respectively, and kinetic studies indicated that both CM-1 and CM-2 are mixed competitive inhibitors of α-glucosidase. Furthermore, docking simulation identified five hydrogen bonds between XO and CM-F; however, only one and two hydrogen bonds are involved in CM-1 and CM-2 binding to α-glucosidase, respectively. Accordingly, curcumin and its analogs have the potential to be used in the treatment of patients with diabetes mellitus and gout.

Keywords: curcumin, α-glucosidase, inhibitor, xanthine oxidase

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Authors: Bhuvanesh Baniya

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Alzheimer disease is illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Holy basil in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of holy basil as potential inhibitors for the treatment of Alzheimer disease. To fulfill this objective, the Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 7 active components in holy basil, 12 predicted neurodegenerative targets of holy basil, and 8063 Alzheimer-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to Alzheimer disease. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Further, the molecular docking results to found that various compounds showed the best binding affinities. Further, MDS top results suggested could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease.

Keywords: holy basil, network pharmacology, neurodegeneration, active phytochemicals, molecular docking and simulation

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Authors: Paweł Stączek, Tomasz Plech, Aleksandra Strzelczyk, Katarzyna Dzitko, Monika Wujec, Edyta Kuśmierz, Piotr Paneth, Agata Paneth

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In this contribution, we will describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile, and molecular modeling evaluation. We have found that one of the tested compounds, 4-benzoyl-1-(2-methyl-furan-3-ylcarbonyl) thiosemicarbazide, remarkably inhibits the activity of S. aureus DNA gyrase with the IC50 below 5 μM. Besides, this compound displays antibacterial activity on Staphylococcus spp. and E. faecalis at non-cytotoxic concentrations in mammalian cells, with minimal inhibitory concentrations (MICs) values at 25 μg/mL. Based on the enzymatic and molecular modeling studies we propose two factors, i.e. geometry of molecule and hydrophobic/hydrophilic balance as important molecular properties for developing thiosemicarbazide derivatives as potent Staphylococcus aureus DNA gyrase inhibitors.

Keywords: bioactivity, drug design, topoisomerase, molecular modeling

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Authors: Tomasz Frączek, Agata Paneth, Rafał Kamiński, Agnieszka Krakowiak, Piotr Paneth

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Azoles are a promising class of the new generation of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. To find novel extensions for this primary scaffold, we explored the 5-position substitution of triazole NNRTIs using molecular docking followed by synthesis of selected compounds. We discovered that heterocyclic substituents in 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with 4-membered thioglycolamide linker. This substitution seems to be viable only for compounds with a shorter 2-membered linker such as in derivatives of 4‐benzyl‐3‐(benzyl-sulfanyl)‐5‐(thiophen‐2‐yl)‐4H‐1,2,4‐triazole reported earlier. A new scaffold of 2‐[(4‐benzyl‐5‐methyl‐4H‐1,2,4‐triazol‐3‐yl)sulfanyl]‐N‐phenylacetamide has been identified in this study.

Keywords: docking, molecular modeling, drug design, novel scaffolds

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Authors: Joshua Chew, Vesa Cheng, David Thomson

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Background: Hereditary angioedema (HAE) or C1 esterase deficiency is a relatively rare entity that has a potential for significant anesthetic complications. Methods: A literature review was performed of published cases of surgery in patients with HAE. Results were limited to English language only and cases were examined for management strategies and successful prevention of acute attacks. Results: The literature revealed the successful use of C1 esterase inhibitors as the most common agent in surgical prophylaxis therapy. Other therapeutic targets described included kallikrein inhibitors and bradykinin B2 receptor antagonists. Conclusions: Therapeutic targets that exist for the management of acute attacks in HAE have been successfully employed in the setting of surgery. The data is currently limited and could not be used as a firm evidence base, but the limited outcomes seen are positive and reassuring for the prospective anesthetic management of this potentially fatal condition.

Keywords: anesthesia, C1 esterase deficiency, hereditary angioedema, surgical prophylaxis

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Authors: Glenda B. Minguito, Jenith L. Banluta

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One of the critical aspects of humanitarian operations is the distribution of relief goods to the affected community. The common assumption is that relief goods are prepositioned during disasters which are not applicable in developing countries like the Philippines. During disasters, the on-the-ground government agencies and responders have to procure, sort, weigh and pack the relief goods. There is a need to review the relief goods preparation as it seriously affects the delivery of necessary aid for human survival. This study also identifies the ideal location of the assembly hub to minimize the distance to the affected community. This paper reveals that location and resources are dependent on the type of disasters encountered at the local level. The Center-of-Gravity method and Multiple Activity Chart were applied in the analysis.

Keywords: humanitarian supply chain, location decision, resource allocation, local level

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Authors: Hyun-Ji Choi

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This paper aims to examine the meaning of ‘state’ as a monopoly of violence, in regard with South Korean democratic transition. Since institutional democratization in 1987, it is conventionally known that governmental authority has exercised its power through law and police force, rather than inclusive or private violence. In other words, 1987 pro-democracy movement has been a critical juncture for a step towards democratic consolidation. However, state coercion may continually be exerted despite institutional specification by law in South Korean context. Explicit case would be amendment of ‘the Law on Assembly and Demonstration’ which determines citizens’ right to take collective action mostly against government actions. This paper investigates amendment process of the law along with social reality since 1987 until 2015 to see how effectively institutionalization has progressed.

Keywords: democratic transition, historical institutionalism, state coercion, the law on Assembly and Demonstration

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Authors: Parvaneh Eskandari, Rachel O'Reilly

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In the last years, controlling the self-assembly behavior of stimuli-responsive nano-objects, including micelles, vesicles, worm-like, etc., at different conditions is considered a pertinent challenge in the polymer community. The aim of the project was to synthesize aggregation-induced emission (AIE)-active stimuli-responsive polymeric nano-objects to control the self-assemblies morphologies of the prepared nano-objects. Two types of nanoobjects, micelle and vesicles, including PDMAEMA-b-P(BzMA-TPEMA) [PDMAEMA: poly(N,Ndimethylaminoethyl methacrylate); P(BzMA-TPEMA): poly[benzyl methacrylate-co- tetraphenylethene methacrylate]] were synthesized by using reversible addition−fragmentation chain-transfer (RAFT)- mediated polymerization-induced self-assembly (PISA), which combines polymerization and self-assembly in a single step. Transmission electron microscope and dynamic light scattering (DLS) analysis were used to confirm the formed self-assemblies morphologies. The controlled self-assemblies were applied as nitrophenolic compounds (NPCs) adsorbents from wastewater, thanks to their CO2-responsive part, PDMAEMA. Moreover, the fluorescence-active part of the prepared nano-objects, P(BzMA-TPEMA), played a key role in the detection of the NPCs at the aqueous solution. The optical properties of the prepared nano-objects were studied by UV/Vis and fluorescence spectroscopies. For responsivity investigations, the hydrodynamic diameter and Zeta-potential (ζ-potential) of the sample's aqueous solution were measured by DLS. In the end, the prepared nano-objects were used for the detection and adsorption of different NPCs.

Keywords: aggregation-induced emission polymers, stimuli-responsive polymers, reversible addition−fragmentation chain-transfer polymerization, polymerization-induced self-assembly, wastewater treatment

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Authors: Filipa Vasconcelos

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The administration of endoplasmic reticulum amino peptidases (ERAP1 or ERAP2) inhibitors can be used for therapeutic approaches against cancer and auto-immune diseases. However, one of the main shortcomings of drug delivery systems (DDS) is associated with the drug off-target distribution, which can lead to an increase in its side effects on the patient’s body. To overcome such limitations, the encapsulation of four representative compounds of ERAP inhibitors into Polycaprolactone (PCL), Polyvinyl-alcohol (PVA), crosslinked PVA, and PVA with nanoparticles (liposomes) electrospun fibrous meshes is proposed as a safe and controlled drug release system. The use of electrospun fibrous meshes as a DDS allows efficient solvent evaporation giving limited time to the encapsulated drug to recrystallize, continuous delivery of the drug while the fibers degrade, prevention of initial burst release (sustained release), tunable dosages, and the encapsulation of other agents. This is possible due to the fibers' small diameters and resemblance to the extracellular matrix (confirmed by scanning electron microscopy results), high specific surface area, and good mechanical strength/stability. Furthermore, release studies conducted on PCL, PVA, crosslinked PVA, and PVA with nanoparticles (liposomes) electrospun fibrous meshes with each of the ERAP compounds encapsulated demonstrated that they were capable of releasing >60%, 50%, 40%, and 45% of the total ERAP concentration, respectively. Fibrous meshes with ERAP_E compound encapsulated achieved higher released concentrations (75.65%, 62.41%, 56.05%, and 65.39%, respectively). Toxicity studies of fibrous meshes with encapsulated compounds are currently being accessed in vitro, as well as pharmacokinetics and dynamics studies. The last step includes the implantation of the drug-loaded fibrous meshes in vivo.

Keywords: drug delivery, electrospinning, ERAP inhibitors, liposomes

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Authors: Esma Kocaoglu, Oktay Talaz, Huseyin Cavdar, Murat Senturk, Deniz Eki̇nci̇

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Glutathione reductase (GR) is a crucial antioxidant enzyme which is responsible for the maintenance of the antioxidant GSH (glutathione) molecule. Antimalarial effects of some chemical molecules are attributed to their inhibition of GR; thus inhibitors of this enzyme are expected to be promising candidates for the treatment of malaria. In this work, GR inhibitory properties of N-Methylpyrrole derivatives are reported. Firstly, GR was purified by means of affinity chromatography using 2’,5’-ADP-Sepharose 4B as ligand. Enzymatic activity was measured by Beutler’s method. Synthesis of the compounds was approved by thin layer chromatography and column chromatography. Different inhibitor concentrations were used and all compounds were tested in triplicate at each concentration used. It was found that all compounds have better inhibitory activity than the strong GR inhibitor N,N-bis(2-chloroethyl)-N-nitrosourea, especially three molecules, 8m, 8n, and 8q, are the best among them with low micromolar I₅₀ values. Findings of our study indicate that these Schiff base derivatives are strong GR inhibitors which can be used as leads for designation of novel antimalaria candidates.

Keywords: glutathione reductase, antimalaria, inhibitor, enzyme

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Authors: S. Shaaban, T. McNamara, S. Hudson

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This paper reports on the performance of deliberately unbalanced, reliable, non-automated and assembly lines that merge, whose workstations differ in terms of their mean operation times. Simulations are carried out on 5- and 8-station lines with 1, 2 and 4 buffer capacity units, % degrees of line imbalance of 2, 5 and 12, and 24 different patterns of means imbalance. Data on two performance measures, namely throughput and average buffer level were gathered, statistically analysed and compared to a merging balanced line counterpart. It was found that the best configurations are a balanced line arrangement and a monotone decreasing order for each of the parallel merging lines, with the first generally resulting in a lower throughput and the second leading to a lower average buffer level than those of a balanced line.

Keywords: average buffer level, merging lines, simulation, throughput, unbalanced

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Authors: Hadjer Didouh, Izzaddine Sameut Bouhaik, Mohammed Hadj Meliani

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This research delves into the intricate dynamics of biofilm adhesion on surfaces, particularly focusing on the widely employed X52 surface in oil and gas industry pipelines. Biofilms, characterized by microorganisms within a self-produced matrix, pose significant challenges due to their detrimental impact on surfaces. Our study integrates advanced molecular techniques and cutting-edge microscopy, such as scanning electron microscopy (SEM), to identify microbial communities and visually assess biofilm adhesion. Simultaneously, we concentrate on the X52 surface, utilizing impedance spectroscopy and potentiodynamic polarization to gather electrochemical responses under various conditions. In conjunction with the broader investigation, we propose a novel approach to mitigate biofilm-induced corrosion challenges. This involves environmentally friendly inhibitors derived from plants, offering a sustainable alternative to conventional chemical treatments. Our inquiry screens and selects inhibitors based on their efficacy in hindering biofilm formation and reducing corrosion rates on the X52 surface. This study contributes valuable insights into the interplay between electrochemical processes and biofilm attachment on the X52 surface. Furthermore, the outcomes of this research have broader implications for the oil and gas industry, where biofilm-related corrosion is a persistent concern. The exploration of eco-friendly inhibitors not only holds promise for corrosion control but also aligns with environmental considerations and sustainability goals. The comprehensive nature of this research aims to enhance our understanding of biofilm dynamics, provide effective strategies for corrosion mitigation, and contribute to sustainable practices in pipeline management within the oil and gas sector.

Keywords: bio-corrosion, biofilm, attachment, X52, metal/bacteria interface

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Authors: Jean Paul M. Milambo

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Purpose: Aromatase inhibitors (AIs) are indicated in the treatment of hormone-receptive breast cancer in postmenopausal women in various settings. Studies have shown cardiovascular events in some developed countries. To date the data is sparce for evidence-based recommendations in African clinical settings due to lack of cancer registries, capacity building and surveillance systems. Therefore, this study was conducted to assess the feasibility of HyBeacon® probe genotyping adjunctive to standard care for timely prediction and diagnosis of Aromatase inhibitors (AIs) associated adverse events in breast cancer survivors in Africa. Methods: Cross sectional study was conducted to assess the knowledge of POCT among six African countries using online survey and telephonically contacted. Incremental cost effectiveness ratio (ICER) was calculated, using diagnostic accuracy study. This was based on mathematical modeling. Results: One hundred twenty-six participants were considered for analysis (mean age = 61 years; SD = 7.11 years; 95%CI: 60-62 years). Comparison of genotyping from HyBeacon® probe technology to Sanger sequencing showed that sensitivity was reported at 99% (95% CI: 94.55% to 99.97%), specificity at 89.44% (95% CI: 87.25 to 91.38%), PPV at 51% (95%: 43.77 to 58.26%), and NPV at 99.88% (95% CI: 99.31 to 100.00%). Based on the mathematical model, the assumptions revealed that ICER was R7 044.55. Conclusion: POCT using HyBeacon® probe genotyping for AI-associated adverse events maybe cost effective in many African clinical settings. Integration of preventive measures for early detection and prevention guided by different subtype of breast cancer diagnosis with specific clinical, biomedical and genetic screenings may improve cancer survivorship. Feasibility of POCT was demonstrated but the implementation could be achieved by improving the integration of POCT within primary health cares, referral cancer hospitals with capacity building activities at different level of health systems. This finding is pertinent for a future envisioned implementation and global scale-up of POCT-based initiative as part of risk communication strategies with clear management pathways.

Keywords: breast cancer, diagnosis, point of care, South Africa, aromatase inhibitors

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Authors: Marcela Dvorakova, Lenka Langhansova, Premysl Landa

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A series of quinazoline derivatives bearing aromatic rings in 2- and 4-positions were prepared and tested for their biological activity. Firstly, the compounds were evaluated for their potential to inhibit various kinases, such as autophagy activating kinase ULK1, 3-Phosphoinositide-dependent kinase 1, and TANK-binding kinase 1. None of the compounds displayed any activity on these kinases. Secondly, the compounds were tested for their anti-inflammatory activity expressed as cyclooxygenase (COX) isoforms and 5-lipoxygenase (5-LOX) inhibition. Three of the compounds showed significant selectivity towards COX-1 isoform (COX-2/COX-1 SI = 20-30). They inhibited COX-1 in a single-digit µM range. There was also one compound that exhibited inhibitory activity towards all three tested enzymes in µM range (IC50COX-1 = 1.9 µM; IC50COX-2 and 5-LOX = 10.1µM. COX-1 inhibition was until recently considered undesirable due to COX-1 constitutive expression in most cell types and tissues. Thus, there are not many compounds known with selective COX-1 activity. However, it is now believed that COX-1 plays an important role in the pathophysiology of several acute and chronic disorders, including cancer or neurodegenerative diseases. Thus, the discovery of effective COX-1 selective inhibitors is desirable and important.

Keywords: cyclooxygenases, kinases, lipoxygenases, quinazolines

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Authors: Kimberley Phoena Fan, Yu Zhang

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ECOSURF™ EH-3 Surfactant (EH3) is a nonionic surfactant and has superior wetting and excellent oil removal properties. It is biodegradable with low toxicity and meets or exceeds US EPA Design for the Environment Criteria, and is widely used as a home cleaner, commercial and industrial degreaser. We have recently found that EH3 also possesses a special function which is characterized as an enhancer to Taq DNA polymerase and ameliorator to reduce the effects of PCR inhibitors, i.e., blood, urea, Guanidinium thiocyanate, Humic acids, polyphenol, and Polysaccharides. This is a new kind of PCR enhancer that does not work on relieving secondary structures of GC-rich templates. We have compared EH3’s effects on Taq DNA Polymerase along with other well-known enhancers, such as DMSO, betaine, and BSA, using GC rich or deficient template and found that, unlike DMSO and Betaine, the EH3 boosting effect on PCR reaction is not through reducing Tm. The results show the same increase of PCR products regardless of the GC contents or secondary structures. The mechanism of EH3 enhancing PCR is through its direct interaction with or stimulation of the DNA polymerase and making the enzymes more resistant to inhibitors in the presence of EH3. This phenomenon has first been observed for EH3, a new type of PCR enzyme enhancer. Subsequent research also shows that a series of similar surfactants boost Taq DNA polymerase as well.

Keywords: EH3, DNA, polymerase, enhancer, raw biological samples

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Authors: Nadine Sangster, Akil James, Rondell Duke, Aaron Ameerali, Terrence Lalla

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The market place of the 21st century is evolving into one of merging national markets, fragmented consumer markets, and rapidly changing product technologies. The use of new technologies has become vital to the manufacturing industry for their survival and sustainability. This work focused on the assembly type industry in a small developing country and aimed at identifying the use of advanced manufacturing technologies and their impact on this sector of the manufacturing industry. It was found that some technologies were being used and that they had improved the effectiveness of those companies but there was still quite a bit of room for improvements. Some of the recommendations included benchmarking against international standards, the adoption of a “made in TT” campaign and the effective utilisation of the technologies to improve manufacturing effectiveness and thus improve competitive advantages and strategies.

Keywords: advanced manufacturing technology, Trinidad and Tobago, manufacturing, industrial engineering

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Authors: W. P. Hu, J. V. Kumar, Jeffrey J. P. Tsai

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The inhibition of SH2 domain regulated protein-protein interactions is an attractive target for developing an effective chemotherapeutic approach in the treatment of disease. Molecular simulation is a useful tool for developing new drugs and for studying molecular recognition. In this study, we searched potential drug compounds for the inhibition of SH2 domain by performing structural similarity search in PubChem Compound Database. A total of 37 compounds were screened from the database, and then we used the LibDock docking program to evaluate the inhibition effect. The best three compounds (AP22408, CID 71463546 and CID 9917321) were chosen for MD simulations after the LibDock docking. Our results show that the compound CID 9917321 can produce a more stable protein-ligand complex compared to other two currently known inhibitors of Src SH2 domain. The compound CID 9917321 may be useful for the inhibition of SH2 domain based on these computational results. Subsequently experiments are needed to verify the effect of compound CID 9917321 on the SH2 domain in the future studies.

Keywords: nonpeptide inhibitor, Src SH2 domain, LibDock, molecular dynamics simulation

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Authors: Shaimaa Eltanani, Thangal Yumnamcha, Ahmed S. Ibrahim

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Purpose: Mitochondria dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to dissect the role of different mitochondrial components, specifically, those of oxidative phosphorylation (OxPhos), in maintaining the barrier function of RECs. Methods: Electric cell-substrate impedance sensing (ECIS) technology was used to assess in real-time the role of different mitochondrial components in the total impedance (Z) of human RECs (HRECs) and its components; the capacitance (C) and the total resistance (R). HRECs were treated with specific mitochondrial inhibitors that target different steps in OxPhos: Rotenone for complex I; Oligomycin for ATP synthase; and FCCP for uncoupling OxPhos. Furthermore, data were modeled to investigate the effects of these inhibitors on the three parameters that govern the total resistance of cells: cell-cell interactions (Rb), cell-matrix interactions (α), and cell membrane permeability (Cm). Results: Rotenone (1 µM) produced the greatest reduction in the Z, followed by FCCP (1 µM), whereas no reduction in the Z was observed after the treatment with Oligomycin (1 µM). Following this further, we deconvoluted the effect of these inhibitors on Rb, α, and Cm. Firstly, rotenone (1 µM) completely abolished the resistance contribution of Rb, as the Rb became zero immediately after the treatment. Secondly, FCCP (1 µM) eliminated the resistance contribution of Rb only after 2.5 hours and increased Cm without considerable effect on α. Lastly, Oligomycin had the lowest impact among these inhibitors on Rb, which became similar to the control group at the end of the experiment without noticeable effects on Cm or α. Conclusion: These results demonstrate differential roles for complex I, complex V, and coupling of OxPhos in maintaining the barrier functionality of HRECs, in which complex I being the most important component in regulating the barrier functionality and the spreading behavior of HRECs. Such differences can be used in investigating gene expression as well as for screening selective agents that improve the functionality of complex I to be used in the therapeutic approach for treating REC-related retinal diseases.

Keywords: human retinal endothelial cells (hrecs), rotenone, oligomycin, fccp, oxidative phosphorylation, oxphos, capacitance, impedance, ecis modeling, rb resistance, α resistance, and barrier integrity

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Authors: A. Nawaz

Abstract:

The present study uses Halliday’s transitivity model to analyze and interpret ideological stance in PM Nawaz Sharif’s political discourse. His famous speech at the 71st UN assembly was analyzed qualitatively using clausal analysis approach to investigate the communicative functions of the linguistic choices made in the address. The study discovers that among the six process types under the transitivity model, material, relational and mental processes appear most frequently in the speech, making up almost 86% of the whole. Verbal processes rank 4th, whereas existential and behavioral are the least occurring processes covering only 2 and 1 percent respectively. The dominant use of material processes suggests that Nawaz Sharif and his government are the main actors working on several concrete projects to produce a sense of developmental progression and continuity. Using relational and mental processes the PM, along with establishing proximity with masses and especially Kashmiri, gives guarantees and promises. The linguistic analysis concludes Kashmir dispute as being the central theme of the address, since it covers more than half of the discourse. The address calls for a strong action instead of formal assurances and wishful thoughts. The study establishes that language structures can yield certain connotations and ideologies which are not overt for readers. This is in affirmation to the supposition that language form performs a communicative function and is not merely fortuitous.

Keywords: Hallidian perspective on language, implicit meanings, Nawaz Sharif, political ideologies, political speeches, transitivity, UN Assembly

Procedia PDF Downloads 209

Authors: M. Hossain, H. P. Zhu, A. B. Yu

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This paper presents a numerical investigation of regime transition of flow of ellipsoidal particles and a comparison with that of spherical particle assembly. Particle assemblies constituting spherical and ellipsoidal particle of 2.5:1 aspect ratio are examined at separate instances in similar flow conditions in a shear cell model that is numerically developed based on the discrete element method. Correlations among elastically scaled stress, kinetically scaled stress, coordination number and volume fraction are investigated, and show important similarities and differences for the spherical and ellipsoidal particle assemblies. In particular, volume fractions at points of regime transition are identified for both types of particles. It is found that compared with spherical particle assembly, ellipsoidal particle assembly has higher volume fraction for the quasistatic to intermediate regime transition and lower volume fraction for the intermediate to inertial regime transition. Finally, the relationship between coordination number and volume fraction shows strikingly distinct features for the two cases, suggesting that different from spherical particles, the effect of the shear rate on the coordination number is not significant for ellipsoidal particles. This work provides a glimpse of currently running work on one of the most attractive scopes of research in this field and has a wide prospect in understanding rheology of more complex shaped particles in light of the strong basis of simpler spherical particle rheology.

Keywords: DEM, granular rheology, non-spherical particles, regime transition

Procedia PDF Downloads 263

Authors: Sema Şenoğlu, Sevgi Karakuş

Abstract:

Hydrazone scaffold is important to design new drug groups and is found to possess numerous uses in pharmaceutical chemistry. Besides, hydrazone derivatives are also known for biological activities such as anticancer, antimicrobial, antiviral, and antifungal. Hydrazone derivatives are promising anticancer agents because they inhibit cancer proliferation and induce apoptosis. Human carbonic anhydrase IX has a high potential to be an antiproliferative drug target, and targeting this protein is also important for obtaining potential anticancer inhibitors. The protein construct was retrieved as a PDB file from the RCSB protein database. This binding interaction of proteins and ligands was performed using Discovery Studio Visualizer. In vitro inhibitory activity of hydrazone derivatives was tested against enzyme carbonic anhydrase IX on the PyRx programme. Most of these molecules showed remarkable human carbonic anhydrase IX inhibitory activity compared to the acetazolamide. As a result, these compounds appear to be a potential target in drug design against human carbonic anhydrase IX.

Keywords: cancer, carbonic anhydrase IX enzyme, docking, hydrazone

Procedia PDF Downloads 82

Authors: F. Ambreen, A.Naheed

Abstract:

Osteoarthritis (OA) is a degenerative disorder affecting millions of people worldwide. Nitric oxide (NO) was found to play a catabolic role in the development of osteoarthritis. It is a toxic free radical gas generated during the metabolism of L-arginine by the enzyme Nitric oxide synthase (NOS). Inducible Nitric Oxide Synthase (iNOS) is one of the isoform of NOS, and its overexpression leads to the excessive formation of NO that results in pathophysiological joint conditions. Several synthetic anti-inflammatory drugs and inhibitors are present to date, but all showed side effects and complications. Therefore, the pursuit of natural disease-modifying drugs remains a top priority. Curcumin is an active component of turmeric, and the past few decades have witnessed intense research devoted to the antioxidant and anti-inflammatory properties of curcumin. The present study focused on curcumin and its derivatives in the search for new iNOS inhibitors for the treatment of osteoarthritis. We conducted a molecular docking study on curcumin and its four derivatives; cyclocurcumin, tetrahydrocurcumin, demethoxycurcumin and curcumin monoglucoside with iNOS using CLC Drug discovery work bench 3.02. We selected two co-crystallized ligands for this study; tetrahydrobiopterin and N-omega-propyl-L-arginine present in complex with the enzyme iNOS. Results showed the best binding affinity of N-omega-propyl-L-arginine with cyclocurcumin and curcumin monoglucoside that exhibit binding energies of -65.2 kcal/mol and -68 kcal/mol respectively. Whereas with tetrahydrobiopterin, best binding scores of -64.7 kcal/mol and -62.2 kcal/mol were found with tetrahydrocurcumin and demethoxycurcumin respectively. This information could open doors of research for the designing of novel drugs using herbs such as curcumin for the treatment of inflammatory joint diseases.

Keywords: curcumin, iNOS, molecular docking, osteoarthritis

Procedia PDF Downloads 129

Authors: A. Elrefaei

Abstract:

The possibility of having sheets with different thicknesses and materials in one assembly facilitates the optimal material distribution within the final product and reduces the weight of the structure. Ability of joining process to assembly these different material combinations is always a challenge to the designer. In this study, 0.6 mm thick 6061-T6 and 2 mm thick 5182-O were robot CMT welded using ER5356 and ER4043 filler metals. The thermal effect of welding resulted in a loss of hardness in the 6061 HAZ. Joints welded by ER5356 filler metal were much higher in fracture load than joints welded by ER4043 and the elongation of joints welded by ER5356 was almost double its corresponding joints welded by ER4043 filler. Owing to the big difference in formability and thickness of base metals, the fracture in forming test occurred in the softened 6061 HAZ out from the weld centerline.

Keywords: aluminum, CMT, mechanical, welding

Procedia PDF Downloads 231